chr4-56523818-C-G

Variant names:

• chr4-56523818-C-G
• NM_001363794.2:c.740C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363794.2(ARL9):​c.740C>G​(p.Pro247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P247L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARL9 NM_001363794.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 0 publications found

Genes affected

ARL9 (HGNC:23592): (ADP ribosylation factor like GTPase 9) ARL9 is a member of the small GTPase protein family with a high degree of similarity to ARF (MIM 103180) proteins of the RAS superfamily.[supplied by OMIM, Nov 2008]

ENSG00000289393 (HGNC:58796):

LOC105377665 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25846094).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363794.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL9	NM_001363794.2	MANE Select	c.740C>G	p.Pro247Arg	missense	Exon 4 of 4	NP_001350723.1	A0A1W2PS79
	ARL9	NM_001401361.1		c.401C>G	p.Pro134Arg	missense	Exon 2 of 2	NP_001388290.1
	ARL9	NM_001401357.1		c.314C>G	p.Pro105Arg	missense	Exon 4 of 4	NP_001388286.1	Q6T311-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL9	ENST00000640821.3	TSL:5 MANE Select	c.740C>G	p.Pro247Arg	missense	Exon 4 of 4	ENSP00000492671.3	A0A1W2PS79
	ARL9	ENST00000360096.3	TSL:1	c.314C>G	p.Pro105Arg	missense	Exon 4 of 4	ENSP00000353210.2	Q6T311-2
	ARL9	ENST00000915214.1		c.656C>G	p.Pro219Arg	missense	Exon 4 of 4	ENSP00000585273.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.64	T
PhyloP100		3.5
PrimateAI	Benign	0.44	T
REVEL	Benign	0.14
Sift4G	Benign	0.16	T
Vest4		0.19
MVP		0.24
MPC		0.44
ClinPred		0.93	D
GERP RS		5.3
gMVP		0.40
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr4-57389984;